Agonist signaling drives neutrophil subpopulations to promote/inhibit colorectal cancer liver metastasis.

Abstract

Liver metastasis is a primary cause of death in colorectal cancer, yet the role of immune cells called neutrophils in this process remains complex. In this study, we identify three distinct neutrophil subtypes: anti-tumor high-density neutrophils, pro-tumor mature low-density neutrophils, and immature low-density neutrophils. Here we show that tumor-derived GM-CSF converts anti-tumor neutrophils into a pro-tumor state via the AKT-NF-κB-NFAT5 signaling axis. These activated neutrophils, when further stimulated by CXCR2 ligands, release web-like structures known as neutrophil extracellular traps which promote cancer spread by enhancing cancer cell growth, suppressing immune responses, and preparing the liver for metastasis. Importantly, we demonstrate that using antibodies depleting neutrophils or drugs inhibiting their pro-tumor activity effectively reduces liver metastasis in mice. Our work defines specific neutrophil subsets as key drivers of cancer progression and highlights their therapeutic potential in preventing metastatic spread.